Time out

Treatment interruption: A risky but essential step in cure research

By Josh Tager and David Evans

If there is ever to be an HIV cure, first there must be people with HIV who are willing to interrupt their antiretroviral therapy (ART). It’s a risky maneuver, for sure, but utterly essential to test whether an experimental intervention is effective.

For a study participant, there are several levels of health risk. First, the drug being tested might not be effective, and in any case, it might induce harmful side effects. Second, interrupting ART is a dicey proposition that could bring health risks, both biological and psychological.

But not only are treatment interruptions risky for participants, they are potentially risky for their sex partners. Studies have confirmed the potency of an undetectable viral load in preventing transmission from a person living with HIV to others.

It’s a big ask to enroll any HIV positive person in a cure study, especially because the world’s top public health experts are finally declaring that people with undetectable viral loads are essentially unable to pass on HIV to others, offering the tantalizing promise for decreased stigma and discrimination for people with HIV.

Reconciling the risks with the benefits—which can vary from one community to another—will require an exhaustive process that includes scientists, ethicists and community advocates. And though biomedical and social science input is required to design and implement these studies, it’s community members who are putting their bodies on the line.

Richard Jefferys points out in “Measuring the HIV Reservoir” that there is currently no accurate way to measure the reservoir if it reaches extremely low levels. That means the only way to detect whether the virus is still present is to take people off ART...and wait. In scientific parlance this is called an analytical treatment interruption (ATI).

Understandably, much of what’s been reported on ATIs, even in the lay press, focuses on the physical health dangers to the study participants. Potential dangers include lasting effects from immune activation (heart problems for one) as well as the potential for the virus to develop resistance to ART medications. Less has been reported about the psychological consequences for participants and the practical implications for their sex lives and relationships.

James McMahon, the Head of the Clinical Research Unit at the Alfred Hospital and Monash University near Melbourne, Australia, has well-considered the knotty challenges of designing studies involving temporary cessation of ART.

“The difficulty with this is that each cure intervention is different, and ATI parameters and frequency of monitoring may need to be individualized for each study,” he said.

“At the moment, there is no standard protocol for a clinical study utilizing an ATI. Some studies test viral load and CD4 counts twice a week, others [every two weeks]. Some restart ART when the viral load [first becomes] detectable, others when it reaches maybe 5,000 copies or 10,000 copies for over 2 weeks.”

Studies have proven that people who participate in clinical trials tend to overestimate the likelihood that they’ll benefit from the study, even when it’s clearly asserted ahead of time that they won’t.

In fact, the AIDS Clinical Trials Group (ACTG), a free-standing HIV clinical trials network funded by the National Institutes of Health, has launched a new study, ACTG5345, that will seek to answer some of these questions. For example, what are the underlying factors that might predict which people can maintain control of the virus when they go off ART?

Liz Barr, an HIV treatment activist and a community advisor to the ACTG, acknowledged the tension between the need to answer some of the critical questions that stand in the way of HIV cure-oriented research and the need to protect people with HIV and their partners from harm.

“Researchers and advocates were torn from the beginning about the study,” she said. “We had a lot of conversations about how to proceed, whether to proceed, how to satisfy the most concerns possible. As you know, the hope with the study is to provide some guidance as to where cure research might go in the future.”

Barr said that the team of researchers, clinicians and community advisors carefully considered not only the health risks involved for study participants, but also the potential psychological and social repercussions.

For one, studies have proven that people who participate in clinical trials tend to overestimate the likelihood that they’ll benefit from the study, even when it’s clearly asserted ahead of time that they won’t. This dynamic could be even more complicated with HIV cure trials that involve an indefinite period off ART, and where the desire to be cured is so intense.

If someone goes off of antiretroviral therapy and maintains viral suppression for even a couple of months, it’s understandable they might wonder if they’ve been cured, or even convince themselves of it, whether or not it’s true. Gary Steinkohl, an HIV-positive New Yorker who interrupted therapy following a stem cell transplant, had exactly this experience. As his virus stayed suppressed for weeks and then months, he reported feeling a profound sense of ease and hope. When the virus returned, he recounted feeling “devastated.”

The stakes are further raised in an ATI study, because a person’s viral load could climb high enough to transmit the virus but before it’s detected by the study investigators.

“Even if there was the potential for long-term viral control off ART due to the study intervention, the risk of onward transmission may still be there,” said McMahon. “If potential participants are correctly informed and have concerns about onward transmission they may well choose not to participate. “

When asked about whether PrEP could be given to a participant’s sex partners, he points out the practical and ethical challenges. Should people with HIV who’d like to participate be turned down if their sex partners refuse to use PrEP? Should HIV-negative partners be asked to consent to the study too?

We’re in uncharted territory, which both Barr and McMahon humbly acknowledge, though both have the same solution for now—extensive discussion among all stakeholders, especially people living with or at risk for HIV.

“I’m not sure how this is best practically done,” McMahon said, although he echoed some of the ACTG study practices. “Clear, open, and honest communication will be critical to the successful conduct of these trials.

POINT/COUNTERPOINT

Biomedical concerns about analytical treatment interruptions

Immune activation

Concern: Chronic immune activation causes more harm to the body than direct killing of immune cells by HIV. In fact, the SMART study and others have shown that HIV keeps the cells so revved up that they can contribute to heart problems, diabetes, cancer, and more. Some experts worry that interrupting ART could increase people’s risk for these problems.

Consideration: Immune activation occurs even when ART suppresses HIV to extremely low levels and in people who naturally control HIV without medication. Treatment interruption studies that allow the virus to rebound to very low levels before resuming treatment may not be worse than staying on ART, but there have been deaths associated with immune activation in studies with longer interruptions.

Expanding the HIV reservoir

Concern: As pointed out in “Measuring the HIV Reservoir” in this issue, the size of the reservoir may determine who can achieve a cure or long-term remission off ART. Some experts worry that taking people off treatment, even for short amounts of time, could increase the size of the reservoir —possibly rendering them less likely to benefit from cure/remission strategies in the future.

Consideration: So far, it does not appear that allowing the virus to return for a period after being suppressed by ART leads to a larger reservoir than was present before ART was stopped.

Acute Retroviral Syndrome (ARS)

Concern: Many people have symptoms when they first become infected—a reaction called Acute Retroviral Syndrome (ARS), where the body is working on hyper-drive trying to control the virus. Most often, people simply feel like they’ve got a bad flu, but the syndrome can sometimes be serious. So, experts worry the risk of ARS could be serious if an ATI allows a person’s virus to peak before they resume treatment.

Consideration: In the natural course of disease outside of HIV cure studies, it’s relatively rare for a person to develop serious symptoms if they have an acute reaction to the virus. However, people who start antiretroviral therapy very early (within days or weeks of infection) never develop an immune response to HIV. That means going off treatment could lead to a rapid spike in virus, with a corresponding—and potentially harmful—activation of the immune system.

Psychosocial concerns about analytical treatment interruptions

Increased transmission risk

Concern: A person with fully suppressed HIV has effectively no chance of transmitting the virus to sex partners, such that top health experts have joined the declaration that undetectable equals untransmittable (U=U). But a person who interrupts ART could have a rapid viral rebound, thereby losing the certainty that they can’t pass on HIV to others.

Consideration:Even constant monitoring for viral rebound (2–3 times per week) won’t eliminate the risk that the virus could climb high enough to allow someone to transmit HIV to their partner(s) before it is detected and they can restart ART. Right now, top researchers are grappling with what to do about this, including possibly providing full prevention services—including PrEP and PEP—to HIV-negative partners of study participants.

Emotional and psychological harms

Concern: The likelihood of receiving any health benefit, let alone being cured or achieving very long-term remission, is exceptionally low with early HIV cure-oriented studies. Experience in the few people who’ve had at least a few months of viral control before rebounding has shown that people often have profound emotional reactions when the virus eventually returns.

Consideration:Unfortunately, there aren’t existing protocols for how to prepare people for this kind of emotional blow if they are one of the rare individuals who sustains viral suppression off of ART for several months or longer. While models for this do exist, particularly in cancer, there have been too few HIV cure studies that involved an ATI for guidelines for researchers and trial designers to be developed.

Difficulties reinitiating ART

Concern: People who have an interruption in a health-maintenance behavior (exercise, diet, medicine taking, etc.) often struggle to resume that behavior at the end of the interruption. Resuming ART is no different. There have been too few cases to know if this will be difficult after ART interruptions from HIV cure studies, but previous non-cure-related ATI studies have found this to be true, and can lead to emergence of HIV drug resistance.

Consideration:There are a number of interventions that have proven effective in helping people reinitiate health-maintenance behaviors, including restarting ART after stopping for one reason or another. Ensuring that they are incorporated into HIV cure studies could minimize risks in this regard.